Pyrrolo[2,3-D]pyrimidine compounds

ABSTRACT

A compound of the formula  
                 
 
     wherein R 1 , R 2  and R 3  are as defined above, which are inhibitors of the enzyme protein kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppressive agents for organ transplants, xeno transplation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn&#39;s disease, Alzheimer&#39;s disease, Leukemia and other autoimmune diseases.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to pyrrolo[2,3-d]pyrimidinecompounds which are inhibitors of protein kinases, such as the enzymeJanus Kinase 3 (hereinafter also referred to as JAK3) and as such areuseful therapy as immunosuppressive agents for organ transplants, xenotransplation, lupus, multiple sclerosis, rheumatoid arthritis,psoriasis, Type I diabetes and complications from diabetes, cancer,asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerativecolitis, Crohn's disease, Alzheimer's disease, Leukemia and otherindications where immunosuppression would be desirable.

[0002] This invention also relates to a method of using such compoundsin the treatment of the above indications in mammals, especially humans,and the phamaceutical compositions useful therefor. JAK3 is a member ofthe Janus family of protein kinases. Although the other members of thisfamily are expressed by essentially all tissues, JAK3 expression islimited to hematopoetic cells. This is consistent with its essentialrole in signaling through the receptors for IL-2, IL-4, IL-7, IL-9 andIL-15 by non-covalent association of JAK3 with the gamma chain common tothese multichain receptors. XSCID patient populations have beenidentified with severely reduced levels of JAK3 protein or with geneticdefects to the common gamma chain, suggesting that immunosuppressionshould result from blocking signaling through the JAK3 pathway. Animalstudies have suggested that JAK3 not only plays a critical role in B andT lymphocyte maturation, but that JAK3 is constitutively required tomaintain T cell function. Modulation of immune activity through thisnovel mechanism can prove useful in the treatment of T cellproliferative disorders such as transplant rejection and autoimmunediseases.

SUMMARY OF THE INVENTION

[0003] The present invention relates to a compound of the formula

[0004] or the pharmaceutically acceptable salt thereof; wherein

[0005] R¹ is a group of the formula

[0006] wherein y is 0, 1 or 2;

[0007] R⁴ is selected from the group consisting of hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynylwherein the alkyl, alkenyl and alkynyl groups are optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₄)alkoxy,(C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano, nitro,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴ is(C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino;

[0008] R⁵ is (C₂-C₉)heterocycloalkyl wherein the heterocycloalkyl groupsmust be substituted by one to five carboxy, cyano, amino, deuterium,hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo, (C₁-C₆)acyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m),R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; or a group ofthe formula

[0009] wherein a is 0, 1, 2, 3 or 4;

[0010] b, c, e, f and g are each independently 0 or 1;

[0011] d is 0, 1, 2, or 3;

[0012] X is S(O)_(n) wherein n is 0, 1 or 2; oxygen, carbonyl or—C(═N-cyano)-;

[0013] Y is S(O)_(n) wherein n is 0, 1 or 2; or carbonyl; and

[0014] Z is carbonyl, C(O)O—, C(O)NR— or S(O)_(n) wherein n is 0, 1 or2;

[0015] R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected fromthe group consisting of hydrogen or (C₁-C₆)alkyl optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino;

[0016] R¹² is carboxy, cyano, amino, oxo, deuterium, hydroxy,trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)—(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m)(C₁-C₆)alkyl, R¹⁵S(O)_(m)R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl;

[0017] R² and R³ are each independently selected from the groupconsisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl wherein the alkyl,alkoxy or cycloalkyl groups are optionally substittued by one to threegroups selected from halo, hydroxy, carboxy, amino (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl,(C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—,(C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein theheteroaryl, heterocycloalkyl and aryl groups are optionally substitutedby one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy,carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy,benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl,(C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl,(C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C6-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-C₉)heteroaryl or(C₂-C₉)heterocycloalkyl.

[0018] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula I. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and pamoate [, 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

[0019] The invention also relates to base addition salts of formula I.The chemical bases that may be used as reagents to preparepharmaceutically acceptable base salts of those compounds of formula Ithat are acidic in nature are those that form non-toxic base salts withsuch compounds. Such non-toxic base salts include, but are not limitedto those derived from such pharmacologically acceptable cations such asalkali metal cations (e.g., potassium and sodium) and alkaline earthmetal cations (e.g., calcium and magnesium), ammonium or water-solubleamine addition salts such as N-methylglucamine-(meglumine), and thelower alkanolammonium and other base salts of pharmaceuticallyacceptable organic amines.

[0020] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight orbranched moieties or combinations thereof.

[0021] The term “alkoxy”, as used herein, includes O-alkyl groupswherein “alkyl” is defined above.

[0022] The term “halo”, as used herein, unless otherwise indicated,includes fluoro, chloro, bromo or iodo.

[0023] The compounds of this invention may contain double bonds. Whensuch bonds are present, the compounds of the invention exist as cis andtrans configurations and as mixtures thereof.

[0024] Unless otherwise indicated, the alkyl and alkenyl groups referredto herein, as well as the alkyl moieties of other groups referred toherein (e.g., alkoxy), may be linear or branched, and they may also becyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl) or be linear or branched and contain cyclic moieties.Unless otherwise indicated, halogen includes fluorine, chlorine,bromine, and iodine.

[0025] (C₂-C₉)Heterocycloalkyl when used herein refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skillin the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon or a Sp³ hybridizednitrogen heteroatom.

[0026] (C₂-C₉)Heteroaryl when used herein refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill inthe art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon atom or a Sp³hybridized nitrogen heteroatom.

[0027] (C₆-C₁₀)aryl when used herein refers to phenyl or naphthyl.

[0028] Compounds of formula (I) may be administered in apharmaceutically acceptable form either alone or in combination with oneor more additional agents which modulate a mammalian immune system orwith antiinflammatory agents. These agents may include but are notlimited to cyclosporin A (e.g. Sandimmune® or Neoral®, rapamycin, FK-506(tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.Cellcept®), azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®. OKT3(e.g. Orthoclone®), AtGam, aspirin, acetaminophen, ibuprofen, naproxen,piroxicam, and antiinflammatory steroids (e.g. prednisolone ordexamethasone). These agents may be administered as part of the same orseparate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice.

[0029] The compounds of this invention include all conformationalisomers (e.g., cis and trans isomers. The compounds of the presentinvention have asymmetric centers and therefore exist in differentenantiomeric and diastereomeric forms. This invention relates to the useof all optical isomers and stereoisomers of the compounds of the presentinvention, and mixtures thereof, and to all pharmaceutical compositionsand methods of treatment that may employ or contain them. In thisregard, the invention includes both the E and Z configurations. Thecompounds of formula I may also exist as tautomers. This inventionrelates to the use of all such tautomers and mixtures thereof.

[0030] This invention also encompasses pharmaceutical compositionscontaining prodrugs of compounds of the formula I. This invention alsoencompasses methods of treating or preventing disorders that can betreated or prevented by the inhibition of protein kinases, such as theenzyme Janus Kinase 3 comprising administering prodrugs of compounds ofthe formula I. Compounds of formula I having free amino, amido, hydroxyor carboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues which arecovalently joined through peptide bonds to free amino, hydroxy orcarboxylic acid groups of compounds of formula I. The amino acidresidues include the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also include, 4-hydroxyproline,hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin,beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine,homoserine, ornithine and methioine sulfone. Prodrugs also includecompounds wherein carbonates, carbamates, amides and alkyl esters whichare covalently bonded to the above substituents of formula I through thecarbonyl carbon prodrug sidechain.

[0031] Preferred compounds of formula I include those wherein a is 0; bis 1; X is carbonyl; c is 0; d is 0; e is 0; f is 0; and g is 0.

[0032] Other preferred compounds of formula I include those wherein a is0; b is 1; X is carbonyl; c is 0; d is 1; e is 0; f is 0, and g is 0.

[0033] Other preferred compounds of formula I include those wherein a is0; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0.

[0034] Other preferred compounds of formula I include those wherein a is0; b is 1; X is —C(═N═cyano)-; c is 1; d is 0; e is 0; f is 0; and g is0.

[0035] Other preferred compounds of formula I include those wherein a is0; b is 0; c is 0; d is 0; e is 0; f is 0; g is 1; and Z is —C(O)—O—.

[0036] Other preferred compounds of formula I include those wherein a is0; b is 1; X is S(O)_(n); n is 2; c is 0; d is 0; e is 0; f is 0; and gis 0.

[0037] Other preferred compounds of formula I include those wherein a is0; b is 1; X is S(O)_(n); n is 2; c is 0; d is 2; e is 0; f is 1; g is1; and Z is carbonyl.

[0038] Other preferred compounds of formula I include those wherein a is0; b is 1; X is S(O)_(n); n is 2; c is 0; d is 2; e is 0; f is 1; and gis 0.

[0039] Other preferred compounds of formula I include those wherein a is0; b is 1; X is carbonyl; c is 1; d is 0; e is 1; Y is S(O)_(n); n is 2;f is 0; and g is 0.

[0040] Other preferred compounds of formula I include those wherein a is0; b is 1; X is S(O)_(n); n is 2; c is 1; d is 0; e is 0; f is 0; and gis 0.

[0041] Other preferred compounds of formula I include those wherein a is1; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0.

[0042] Other preferred compounds of formula I include those wherein a is0; b is 1; X is S(O)_(n); c is 0; d is 1; e is 1; Y is S(O)_(n); n is 2;f is 0; and g is 0.

[0043] Other preferred compounds of formula I include those wherein a is0; b is 1; X is S(O)_(n); c is 0; d is 1; e is 1; Y is S(O)_(n); n is 2;f is 1; and g is 0.

[0044] Other preferred compounds of formula I include those wherein a is0; b is 1; X is oxygen; c is 0; d is 1; e is 1; Y is S(O)_(n); n is 2; fis 1; and g is 0.

[0045] Other preferred compounds of formula I include those wherein a is0; b is 1; X is oxygen; c is 0; d is 1; e is 1; Y is S(O)_(n); n is 2; fis 0; and g is 0.

[0046] Other preferred compounds of formula I include those wherein a is0; b is 1; X is carbonyl; c is 1; d is 1; e is 1; Y is S(O)_(n); f is 0;and g is 0.

[0047] Other preferred compounds of formula I include those wherein a is0; b is 1; X is carbonyl; c is 1; d is 1; e is 1; Y is S(O)_(n); n is 2;f is 1; and g is 0.

[0048] Other preferred compounds of formula I include those wherein R¹²is cyano, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkynyl,cyano(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m) wherein m is 0, 1 or 2.

[0049] Specific preferred compounds of formula I include those whereinsaid compound is selected from the group consisting of:

[0050]Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;

[0051]4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid methyl ester;

[0052]3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;

[0053]4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-y)-amino]-piperidine-1-carboxylicacid dimethylamide;

[0054]({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-amino)-aceticacid ethyl ester;

[0055]3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile;

[0056]3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperdin-1-yl}-propan-1-one;

[0057]1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-but-3-yn-1-one;

[0058]1-{3-[(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-piperidin-1-yl}-propan-1-one;

[0059]1-{3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-piperidin-1-yl}-propan-1-one;

[0060]N-cyano-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-N′-propyl-piperidine-1-carboxamidine;and

[0061]N-cyano-4,N′,N′-Trimethyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxamidine.

[0062] The present invention also relates to a pharmaceuticalcomposition for (a) treating or preventing a disorder or conditionselected from organ transplant rejection, xeno transpiation, lupus,multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes andcomplications from diabetes, cancer, asthma, atopic dermatitis,autoimmune thyroid disorders, ulcerative colitis, Crohn's disease,Alzheimer's disease, Leukemia, and other autoimmune diseases or (b) theinhibition of protein kinases or Janus Kinase 3 (JAK3) in a mammal,including a human, comprising an amount of a compound of formula I or apharmaceutically acceptable salt thereof, effective in such disorders orconditions and a pharmaceutically acceptable carrier.

[0063] The present invention also relates to a method for the inhibitionof protein typrosine kinases or Janus Kinase 3 (JAK3) in a mammal,including a human, comprising administering to said mammal an effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof.

[0064] The present invention also relates to a method for treating orpreventing a disorder or condition selected from organ transplantrejection, xeno transplation, lupus, multiple sclerosis, rheumatoidarthritis, psoriasis, Type I diabetes and complications from diabetes,cancer, asthma, atopic dermatitis, autoimmune thyroid disorders,ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia, andother autoimmune diseases in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of formula I or apharmaceutically acceptable salt thereof, effective in treating such acondition.

DETAILED DESCRIPTION OF THE INVENTION

[0065] The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated R², R³,R⁴ and R⁵ in the reaction Schemes and the discussion that follow aredefined as above.

[0066] In reaction 1 of Preparation A, the4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI, wherein R ishydrogen or a protecting group such as benzenesulfonyl or benzyl, isconverted to the 4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound offormula XX, wherein Y is chloro, bromo or iodo, by reacting XXI withN-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide. Thereaction mixture is heated to reflux, in chloroform, for a time periodbetween about 1 hour to about 3 hours, preferably about 1 hour.Alternatively, in reaction 1 of Preparation A, the4-chloropyrrolo[2,3-d]pyrimidine of formula XXI, wherein R is hydrogen,is converted to the corresponding4-chloro-5-nitropyrrolo[2,3-d]pyrimidine of formula XX, wherein Y isnitro, by reacting XXI with nitric acid in sulfuric acid at atemperature between about −10° C. to about 10° C., preferably about 0°C., for a time period between about 5 minutes to about 15 minutes,preferably about 10 minutes. The compound of formula XXI, wherein Y isnitro, is converted to the corresponding4-chloro-5-aminopyrrolo[2,3-d]pyrimidine of the formula XX, wherein Y isamino, by reacting XXI under a variety of conditions known to oneskilled in the art such as palladium hydrogenolysis or tin(IV)chlorideand hydrochloric acid.

[0067] In reaction 2 of Preparation A, the4-chloro-5-halopyrrolo[2,3-d]pyrimidine compound of formula XX, whereinR is hydrogen, is converted to the corresponding compound of formulaXIX, wherein R² is (C₁-C₆)alkyl or benzyl, by treating XX withN-butyllithium, at a temperature of about −78° C., and reacting thedianion intermediate so formed with an alkylhalide or benzylhalide at atemperature between about −78° C. to room temperature, preferably roomtemperature. Alternatively, the dianion so formed is reacted withmolecular oxygen to form the corresponding4-chloro-5-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XIX,wherein R² is hydroxy. The compound of formula XX, wherein Y is bromineor iodine and R is benzenesulfonate, is converted to the compound offormula XIX, wherein R² is (C₆-C₁₂)aryl or vinyl, by treating XX withN-butyllithium, at a temperature of about −78° C., followed by theaddition of zinc chloride, at a temperature of about −78° C. Thecorresponding organo zinc intermediate so formed is then reacted witharyliodide or vinyl iodide in the presence of a catalytic quantity ofpalladium. The reaction mixture is stirred at a temperature betweenabout 50° C. to about 80° C., preferably about 70° C., for a time periodbetween about 1 hour to about 3 hours, preferably about 1 hour.

[0068] In reaction 3 of Preparation A, the compound of formula XIX isconverted to the corresponding compound of formula XVI by treating XIXwith N-butyllithium, lithium diisopropylamine or sodium hydride, at atemperature of about −78° C., in the presence of a polar aproticsolvent, such as tetrahydrofuran. The anionic intermediate so formed isfurther reacted with (a) alkylhalide or benzylhalide, at a temperaturebetween about −78° C. to room temperature, preferably −78 ° C., when R³is alkyl or benzyl; (b) an aldehyde or ketone, at a temperature betweenabout −78° C. to room temperature, preferably −78° C., when R³ isalkoxy; and (c) zinc chloride, at a temperature between about −78° C. toroom temperature, preferably −78° C., and the corresponding organozincintermediate so formed is then reacted with aryliodide or vinyl iodidein the presence of a catalytic quantity of palladium. The resultingreaction mixture is stirred at a temperature between about 50° C. toabout 80° C., preferably about 70° C., for a time period between about 1hour to about 3 hours, preferably about 1 hour. Alternatively, the anionso formed is reacted with molecular oxygen to form the corresponding4-chloro-6-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XVI,wherein R³ is hydroxy.

[0069] In reaction 1 of Preparation B, the4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI is converted tothe corresponding compound of formula XXII, according to the proceduredescribed above in reaction 3 of Preparation A.

[0070] In reaction 2 of Preparation B, the compound of formula XXII isconverted to the corresponding compound of formula XVI, according to theprocedures described above in reactions 1 and 2 of Preparation A.

[0071] In reaction 1 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XVII is converted to the corresponding compound offormula XVI, wherein R is benzenesulfonyl or benzyl, by treating XVIIwith benzenesulfonyl chloride, benzylchloride or benzylbromide in thepresence of a base, such as sodium hydride or potassium carbonate, and apolar aprotic solvent, such as dimethylformamide or tetrahydrofuran. Thereaction mixture is stirred at a temperature between about 0° C. toabout 70° C., preferably about 30° C., for a time period between about 1hour to about 3 hours, preferably about 2 hours.

[0072] In reaction 2 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XVI is converted to the corresponding4-aminopyrrolo[2,3-d]pyrimidine compound of formula XV by coupling XVIwith an amine of the formula HNR⁴R⁵. The reaction is carried out in analcohol solvent, such as tert-butanol, methanol or ethanol, or otherhigh boiling organic solvents, such as dimethylformamide, triethylamine,1,4-dioxane or 1,2-dichloroethane, at a temperature between about 60° C.to about 120° C., preferably about 80° C. Typical reaction times arebetween about 2 hours to about 48 hours, preferably about 16 hours. WhenR⁵ is a nitrogen containing heterocycloalkyl group, each nitrogen mustbe protected by a protecting group, such a benzyl. Removal of the R⁵protecting group is carried out under conditions appropriate for thatparticular protecting group in use which will not affect the Rprotecting group on the pyrrolo[2,3-d]pyrimidine ring. Removal of the R⁵protecting group, when benzyl, is carried out in an alcohol solvent,such as ethanol, in the present of hydrogen and a catalyst, such aspalladium hydroxide on carbon. The R⁵ nitrogen containinghetrocycloalkyl group so formed may be further reacted with a variety ofdifferent electrophiles of formula II. For urea formation, electrophilesof formula II such as isocyanates, carbamates and carbamoyl chloridesare reacted with the R⁵ nitrogen of the heteroalkyl group in a solvent,such as acetonitrile or dimethylformamide, in the presence of a base,such as sodium or potassium carbonate, at a temperature between about20° C. to about 100° C. for a time period between about 24 hours toabout 72 hours. For amide and sulfonamide formation, electrophiles offormula II, such as acylchlorides and sulfonyl chlorides, are reactedwith the R⁵ nitrogen of the heteroalkyl group in a solvent such asmethylene chloride in the presence of a base such as pyridine at ambienttemperatures for a time period between about 12 hours to about 24 hours.Amide formation may also be carried out by reacting a carboxylic acidwith the heteroalkyl group in the presence of a carbodiimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in a solvent such asmethylene chloride at ambient temperatures for 12-24 hours. For alkylformation, electrophiles of formula II, such as α,β-unsaturated amides,acids, nitriles, esters, and α-halo amides, are reacted with the R⁵nitrogen of the heteroalkyl group in a solvent such as methanol atambient temperatures for a time period between about 12 hours to about18 hours. Alkyl formation may also be carried out by reacting aldehydeswith the heteroalkyl group in the presence of a reducing agent, such assodium cyanoborohydride, in a solvent, such as methanol, at ambienttemperature for a time period between about 12 hours to about 18 hours.

[0073] In reaction 3 of Scheme 1, removal of the protecting group fromthe compound of formula XV, wherein R is benzenesulfonyl, to give thecorresponding compound of formula I, is carried out by treating XV withan alkali base, such as sodium hydroxide or potassium hydroxide, in analcohol solvent, such as methanol or ethanol, or mixed solvents, such asalcohol/tetrahydrofuran or alcohol/water. The reaction is carried out atroom temperature for a time period between about 15 minutes to about 1hour, preferably 30 minutes. Removal of the protecting group from thecompound of formula XV, wherein R is benzyl, is conducted by treating XVwith sodium in ammonia at a temperature of about −78° C. for a timeperiod between about 15 minutes to about 1 hour.

[0074] In reaction 1 of Scheme 2, the 4-chloropyrrolo[2,3-d]pyrimidinecompound of formula XX is converted to the corresponding4-aminopyrrolo[2,3-d]pyrimidine compound of formula XXIV, according tothe procedure described above in reaction 2 of Scheme 1.

[0075] In reaction 2 of Scheme 2, the4-amino-5-halopyrrolo[2,3-d]pyrimidine compound of formula XXIV, whereinR is benzenesulfonate and Z is bromine or iodine, is converted to thecorresponding compound of formula XXIII by reacting XXIV with (a)arylboronic acid, when R² is aryl, in an aprotic solvent, suchtetrahydrofuran or dioxane, in the presence of a catalytic quantity ofpalladium (0) at a temperature between about 50° C. to about 100° C.,preferably about 70° C., for a time period between about 2 hours toabout 48 hours, preferably about 12 hours; (b) alkynes, when R² isalkynyl, in the presence of a catalytic quantity of copper (I) iodideand palladium (0), and a polar solvent, such as dimethylformamide, atroom temperature, for a time period between about 1 hour to about 5hours, preferably about 3 hours; and (c) alkenes or styrenes, when R² isvinyl or styrenyl, in the presence of a catalytic quantity of palladiumin dimethylformamide, dioxane or tetrahydrofuran, at a temperaturebetween about 80° C. to about 100° C., preferably about 100° C., for atime period between about 2 hours to about 48 hours, preferably about 48hours.

[0076] In reaction 3 of Scheme 2, the compound of formula XXIII isconverted to the corresponding compound of formula XV, according to theprocedure described above in reaction 3 of Preparation A.

[0077] In reaction 1 of Scheme 3, the compound of formula XVII isconverted to the corresponding compound of formula I, according to theprocedure described above in reaction 2 of Scheme 1.

[0078] The compounds of the present invention that are basic in natureare capable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate the compound of the presentinvention from the reaction mixture as a pharmaceutically unacceptablesalt and then simply convert the latter back to the free base compoundby treatment with an alkaline reagent and subsequently convert thelatter free base to a pharmaceutically acceptable acid addition salt.The acid addition salts of the base compounds of this invention arereadily prepared by treating the base compound with a substantiallyequivalent amount of the chosen mineral or organic acid in an aqueoussolvent medium or in a suitable organic solvent, such as methanol orethanol. Upon careful evaporation of the solvent, the desired solid saltis readily obtained. The desired acid salt can also be precipitated froma solution of the free base in an organic solvent by adding to thesolution an appropriate mineral or organic acid.

[0079] Those compounds of the present invention that are acidic innature, are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of the presentinvention. Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

[0080] The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) or rectal administration or in a formsuitable for administration by inhalation or insufflation. The activecompounds of the invention may also be formulated for sustaineddelivery.

[0081] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g., magnesium stearate,talc or silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters or ethyl alcohol); and preservatives(e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

[0082] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0083] The active compounds of the invention may be formulated forparenteral administration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use. The activecompounds of the invention may also be formulated in rectal compositionssuch as suppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

[0084] For intranasal administration or administration by inhalation,the active compounds of the invention are conveniently delivered in theform of a solution or suspension from a pump spray container that issqueezed or pumped by the patient or as an aerosol spray presentationfrom a pressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0085] A proposed dose of the active compounds of the invention fororal, parenteral or buccal administration to the average adult human forthe treatment of the conditions referred to above (e.g., rheumatoidarthritis) is 0.1 to 1000 mg of the active ingredient per unit dosewhich could be administered, for example, 1 to 4 times per day.

[0086] Aerosol formulations for treatment of the conditions referred toabove (e.g., asthma) in the average adult human are preferably arrangedso that each metered dose or “puff” of aerosol contains 20 μg to 1000 μgof the compound of the invention. The overall daily dose with an aerosolwill be within the range 0.1 mg to 1000 mg. Administration may beseveral times daily, for example 2, 3, 4 or 8 times, giving for example,1, 2 or 3 doses each time.

[0087] A compound of formula (I) administered in a pharmaceuticallyacceptable form either alone or in combination with one or moreadditional agents which modulate a mammlian immune system or withantiinflammatory agents, agents which may include but are not limited tocyclosporin A (e.g. Sandimmune® or Neoral®, rapamycin, FK-506(tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g.Cellcept®, azathioprine (e.g. Imuran®), daclizumab (e.g. Zenapax®), OKT3(e.g. Orthocolone®), AtGam, aspirin, acctaminophen, ibuprofen, naproxen,piroxicam, and antiinflammatory steroids (e.g. prednisolone ordexamethasone); and such agents may be administered as part of the sameor separate dosage forms, via the same or different routes ofadministration, and on the same or different administration schedulesaccording to standard pharmaceutical practice.

[0088] FK506 (Tacrolimus) is given orally at 0.10-0.15 mg/kg bodyweight, every 12 hours, within first 48 hours postoperative. Does ismonitored by serum Tacrolimus trough levels.

[0089] Cyclosporin A (Sandimmune oral or intravenous formulation, orNeoral®, oral solution or capsules) is given orally at 5 mg/kg bodyweight, every 12 hours within 48 hours postoperative. Dose is monitoredby blood Cyclosporin A trough levels.

[0090] The active agents can be formulated for sustained deliveryaccording to methods well known to those of ordinary skill in the art.Examples of such formulations can be found in U.S. Pat. Nos. 3,538,214,4,060,598, 4,173,626, 3,119,742, and 3,492,397.

[0091] The ability of the compounds of formula I or theirpharmaceutically acceptable salts to inhibit Janus Kinase 3 and,consequently, demonstrate their effectiveness for treating disorders orconditions characterized by Janus Kinase 3 is shown by the following invitro assay tests.

Biological Assay

[0092] JAK3 (JH1:GST) Enzymatic Assay

[0093] The JAK3 kinase assay utilizes a protein expressed inbaculovirus-infected SF9 cells (a fusion protein of GST and thecatalytic domain of human JAK3) purified by affinity chromatography onglutathione-Sepaharose. The substrate for the reaction is poly-Glutamicacid-Tyrosine (PGT (4:1), Sigma catalog # P0275), coated onto Nunc MaxiSorp plates at 100 μg/ml overnight at 37° C. The morning after coating,the plates are washed three times and JAK3 is added to the wellscontaining 100 μl of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24mM MgCl2)+0.2 uM ATP +1 mM Na orthovanadate.) The reaction proceeds for30 minutes at room temperature and the plates is washed three moretimes. The level of phosphorylated tyrosine in a given well isquantitated by standard ELISA assay utilizing an anti-phosphotyrosineantibody (ICN PY20, cat. #69-151-1).

[0094] Inhibition of Human IL-2 Dependent T-Cell Blast Proliferation

[0095] This screen measures the inhibitory effect of compounds on IL-2dependent T-Cell blast proliferation in vitro. Since signaling throughthe IL-2 receptor requires JAK-3, cell active inhibitors of JAK-3 shouldinhibit IL-2 dependent T-Cell blast proliferation.

[0096] The cells for this assay are isolated from fresh human blood.After separation of the mononuclear cells using AccuspinSystem-Histopaque-1077 (Sigma # A7054), primary human T-Cells areisolated by negative selection using Lympho-Kwik T (One Lambda, Inc.,Cat # LK-50T). T-Cells are cultured at 1-2×10⁶/ml in Media (RPMI+10%heat-inactivated fetal calf serum (Hyclone Cat # A-1111-L) +1%Penicillin/Streptomycin (Gibco)) and induce to proliferate by theaddition of 10 ug/ml PHA (Murex Diagnostics, Cat # HA 16). After 3 daysat 37° C. in 5% CO₂, cells are washed 3 times in Media, resuspended to adensity of 1-2×10₆ cells/ml in Media plus 100 Units/ml of humanrecombinant IL-2 (R&D Systems, Cat # 202-IL). After 1 week the cells areIL-2 dependent and can be maintained for up to 3 weeks by feeding twiceweekly with equal volumes of Media+100 Units/ml of IL-2.

[0097] To assay for a test compounds ability to inhibit IL-2 dependentT-Cell proliferation, IL-2 dependent cells are washed 3 times,resuspended in media and then plated (50,000 cells/well/0.1 ml) in aFlat-bottom 96-well microtiter plate (Falcon # 353075). From a 10 mMstock of test compound in DMSO, serial 2-fold dilutions of compound areadded in triplicate wells starting at 10 uM. After one hour, 10 Units/mlof IL-2 is added to each test well. Plates are then incubated at 37° C.,5% CO₂ for 72 hours. Plates are then pulsed with ³H-thymidine (0.5uCi/well) (NEN Cat # NET-027A), and incubated an additional 18 hours.Culture plates are then harvested with a 96-well plate harvester and theamount of ³H-thymidine incorporated into proliferating cells isdetermined by counting on a Packard Top Count scintillation counter.Data is analyzed by plotting the % inhibition of proliferation versesthe concentration of test compound. An IC₅₀ value (uM) is determinedfrom this plot.

[0098] The following Examples illustrate the preparation of thecompounds of the present invention but it is not limited to the detailsthereof. Melting points are uncorrected. NMR data are reported in partsper million (δ) and are referenced to the deuterium lock signal from thesample solvent (deuteriochloroform unless otherwise specified).Commercial reagents were utilized without further purification. THFrefers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. LowResolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard5989®, utilizing chemical ionization (ammonium), or a Fisons (or MicroMass) Atmospheric Pressure Chemical Ionization (APCI) platform whichuses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as theionizing agent. Room or ambient temperature refers to 20-25° C.

EXAMPLE 11-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}ethanone

[0099] Method A

[0100] (1-Benzyl-4-methyl-piperidin-3-yl)-methyl-amine

[0101] To a stirred solution of 1-benzyl-4-methyl-piperidin-3-one (2.3grams, 11.5 mmol), prepared by the methods of lorio, M. A. and Damia,G., Tetrahedron, 26, 5519 (1970) and Grieco et al., Journal of theAmerican Chemical Society, 107, 1768 (1985), (modified using 5% methanolas a co-solvent), both references are incorporated by reference in theirentirety, dissolved in 23 mL of 2 M methylamine in tetrahydrofuran wasadded 1.4 mL (23 mmol) of acetic acid and the resulting mixture stirredin a sealed tube for 16 hours at room temperature. Triacetoxy sodiumborohydride (4.9 grams, 23 mmol) was added and the new mixture stirredat room temperature in a sealed tube for 24 h, at which time, thereaction was quenched upon addition of 1 N sodium hydroxide (50 mL). Thereaction mixture was then extracted 3×80 mL with ether, the combinedether layers dried over sodium sulfate (Na₂SO₄) and concentrated todryness in vacuo affording 1.7 grams (69%) of the title compound as awhite solid. LRMS: 219.1 (M+1).

[0102] Method B

[0103](1-Benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolor[2,3-d]pyrimidin-4-yl)-amine

[0104] A solution of 4-chloropyrrolo[2,3-d]pyrimidine (2.4 grams, 15.9mmol), prepared by the method of Davoll, J. Am. Chem. Soc., 82, 131(1960), which is incorporated by reference in its entirety, and theproduct from Method A (1.7 grams, 7.95 mmol) dissolved in 2 equivalentsof triethylamine was heated in a sealed tube at 100° C. for 3 days.Following cooling to room temperature and concentration under reducedpressure, the residue was purified by flash chromatography (silica; 3%methanol in dichloromethane) affording 1.3 grams (50%) of the titlecompound as a colorless oil. LRMS: 336.1 (M+1).

[0105] Method C

[0106]Methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0107] To the product from Method B (0.7 grams, 2.19 mmol) dissolved in15 mL of ethanol was added 1.5 mL of 2 N hydrochloric acid and thereaction mixture degassed by nitrogen purge. To the reaction mixture wasthen added 0.5 grams of 20% palladium hydroxide on carbon (50% water)(Aldrich) and the resulting mixture shaken (Parr-Shaker) under a 50 psiatmosphere of hydrogen at room temperature for 2 days. The Celitefiltered reaction mixture was concentrated to dryness in vacuo and theresidue purified by flash chromatography (silica; 5% methanol indichoromethane) affording 0.48 grams (90%) of the title compound. LRMS:246.1 (M+1).

[0108] Method D

[0109]1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

[0110] To a stirred solution of the product from Method C (0.03 grams,0.114 mmol) dissolved in 5 mL of 10:1 dichloromethane/pyridine was added(0.018 grams, 0.228 mmol) of acetylchloride and the resulting mixturestirred at room temperature for 18 hours. The reaction mixture was thenpartitioned between dichloromethane and saturated sodium bicarbonate(NaHCO₃). The organic layer was washed again with saturated NaHCO₃,dried over sodium sulfate and concentrated to dryness in vacuo. Theresidue was purified by preparative thin layer chromatography (PTLC)(silica; 4% methanol in dichloromethane) affording 0.005 mg (15%) of thetitle compound as a colorless oil. LRMS: 288.1 (M+1).

[0111] The title compounds for examples 2-26 were prepared by a methodanalogous to that described in Example 1.

EXAMPLE 2[1-(2-Amino-ethanesulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0112][1-(2-Amino-ethanesulfonyl)-4-methyl-piperidin-3-yl]-methyl-amine. LRMS:353.

EXAMPLE 3(1-Ethanesulfonyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0113] (1-Ethanesulfonyl-4-methyl-piperidin-3-yl)-methyl-amine. LRMS:338.

EXAMPLE 4[1-(Butane-1-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0114] [1-(Butane-1-sulfonyl)-4-methyl-piperidin-3-yl]-methyl-amine.LRMS: 366.

EXAMPLE 54-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid isobutyl ester

[0115] 4-Methyl-3-methylamino-piperidine-1-carboxylic acid isobutylester. LRMS: 346.

EXAMPLE 6N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-propionamide

[0116]N-[2-(4-Methyl-3-methylamino-piperidine-1-sulfonyl)-ethyl]-propionamide.LRMS: 409.

EXAMPLE 7(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-carbamicacid methyl ester

[0117] [2-(4-Methyl-3-methylamino-piperidine-1-sulfonyl)-ethyl]-carbamicacid methyl ester. LRMS: 411.

EXAMPLE 8N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-isobutyramide

[0118]N-[2-(4-Methyl-3-methylamino-piperidine-1-sulfonyl)-ethyl]-isobutyramide.LRMS: 423.

EXAMPLE 9(1-Methanesulfonyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0119] (1-Methanesulfonyl-piperidin-3-yl)-methyl-amine. LRMS: 310.

EXAMPLE 10(1-Ethanesulfonyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0120] (1-Ethanesulfonyl-piperidin-3-yl)-methyl-amine. LRMS: 324.

EXAMPLE 11Methyl-[1-(Propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0121] (1-Propylsulfonyl-piperidin-3-yl)-methyl-amine. LRMS: 338.

EXAMPLE 12[1-(Butane-1-sulfonyl)-piperidin-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0122] (1-Butylsulfonyl-piperidin-3-yl)-methyl-amine. LRMS: 352.

Exampl 132,2-Dimethyl-N-(2-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-sulfonyl}-ethyl)-propionamide

[0123]2,2-Dimethyl-N-[2-(4-methyl-3-methylamino-piperidine-1-sulfonyl)-ethyl]propionamide.LRMS: 437.

EXAMPLE 143-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-piperidin-1-yl}-3-oxo-propionitrile

[0124] 3-(4-Methyl-3-methylamino-piperidin-1-yl)-3-oxo-propionitrile.LRMS: 313.

EXAMPLE 15(3-{4-Methyl-3-[methyl-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}3-oxo-propyl)-carbamicacid tert-butyl ester

[0125] [3-(4-Methyl-3-methylamino-piperidin-1-yl)-3-oxo-propyl]-carbamicacid tert-butyl ester. LRMS: 417.

EXAMPLE 16Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine

[0126] Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-amine.LRMS: 352.

EXAMPLE 173-Amino-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one

[0127] 3-Amino-1-(4-methyl-3-methylamino-piperidin-1-yl)-propan-1-one.LRMS: 317.

EXAMPLE 182-Methoxy-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

[0128] 2-Methoxy-1-(4-methyl-3-methylamino-piperidin-1-yl)-ethanone.LRMS: 318.

EXAMPLE 192-Dimethylamino-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-ethanone

[0129]2-Dimethylamino-1-(4-methyl-3-methylamino-piperidin-1-yl)-ethanone.LRMS: 331.

EXAMPLE 20(3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propyl)-carbamicacid tert-butyl ester

[0130] [3-(4-Methyl-3-methylamino-piperidin-1-yl)-3-oxo-propyl]-carbamicacid tert-butyl ester. LRMS: 417.

EXAMPLE 213,3,3-Trifluoro-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one

[0131]3,3,3-Trifluoro-1-(4-methyl-3-methylamino-piperidin-1-yl)-propan-1-one.

EXAMPLE 22N-(2-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-acetamide

[0132]N-[2-(4-Methyl-3-methylamino-piperidin-1-yl)-2-oxo-ethyl]-acetamide.LRMS: 345.

EXAMPLE 233-Ethoxy-1-{4-methyl-3-[methyl-(7H-pyrrolor[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one

[0133] 3-Ethoxy-1-(4-methyl-3-methylamino-piperidin-1-yl)-propan-1-one.LRMS: 346.

EXAMPLE 244-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid methylamide

[0134] 4-Methyl-3-methylamino-piperidine-1-carboxylic acid methylamide.LRMS: 303.

EXAMPLE 254-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid diethylamide

[0135] 4-Methyl-3-methylamino-piperidine-1-carboxylic acid diethylamide.LRMS: 345.

EXAMPLE 26Methyl-[4-methyl-1-(2-methylamino-ethanesulfonyl)-piperidin-3-yl]-(7H-pyrrolor[2,3-d]pyrimidin-4-yl)-amine

[0136]Methyl-[4-methyl-1-(2-methylamino-ethanesulfonyl)-piperidin-3-yl]3-amine.LRMS: 367.

1. A compound of the formula

or the pharmaceutically acceptable salt thereof; wherein R¹ is a groupof the formula

wherein y is 0, 1 or 2; R⁴ is selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl wherein the alkyl, alkenyl and alkynyl groups areoptionally substituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₄)alkoxy, (C₁-C₆)acyloxy, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino,cyano, nitro, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl or (C₁-C₆)acylamino; or R⁴is (C₃-C₁₀)cycloalkyl wherein the cycloalkyl group is optionallysubstituted by deuterium, hydroxy, amino, trifluoromethyl,(C₁-C₆)acyloxy, (C₁-C₆)acylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, cyano, cyano(C₁-C₆)alkyl,trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkyl or(C₁-C₆)acylamino; R⁵ is (C₂-C₉)heterocycloalkyl wherein theheterocycloalkyl groups must be substituted by one to five carboxy,cyano, amino, deuterium, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo,(C₁-C₆)acyl, (C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH,(C₁-C₆)alkylamino-CO—, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl,(C₁-C₆)alkylamino, amino(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino(C₁-C₆)acyl, R¹⁵R¹⁶N—CO—O—, R ¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m),R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; or a group ofthe formula

wherein a is 0, 1, 2, 3 or 4; b, c, e, f and g are each independently 0or 1; d is 0, 1, 2, or 3; X is S(O)_(n) wherein n is 0, 1 or 2; oxygen,carbonyl or —C(═N-cyano)-; Y is S(O)_(n) wherein n is 0, 1 or 2; orcarbonyl; and Z is carbonyl, C(O)O—, C(O)NR— or S(O)_(n) wherein n is 0,1 or 2; R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected fromthe group consisting of hydrogen or (C₁-C₆)alkyl optionally substitutedby deuterium, hydroxy, amino, trifluoromethyl, (C₁-C₆)acyloxy,(C₁-C₆)acylamino, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, cyano,cyano(C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl, nitro, nitro(C₁-C₆)alkylor (C₁-C₆)acylamino; R¹² is carboxy, cyano, amino, oxo, deuterium,hydroxy, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo, (C₁-C₆)acyl, (C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH, (C₁-C₆)alkylamino-CO—,(C₂-C₆)alkenyl, (C₂-C₆) alkynyl, (C₁-C₆)alkylamino, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkoxy(C₁-C₆)alkyl, (C₁-C₆)acyloxy(C₁-C₆)alkyl, nitro,cyano(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, nitro(C₁-C₆)alkyl, trifluoromethyl,trifluoromethyl(C₁-C₆)alkyl, (C₁-C₆)acylamino,(C₁-C₆)acylamino(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C₁-C₆)acylamino,amino(C₁-C₆)acyl, amino(C₁-C₆)acyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)acyl, ((C₁-C₆)alkyl)₂amino (C₁-C₆)acyl,R¹⁵R¹⁶N—CO—O—, R¹⁵R¹⁶N—CO—(C₁-C₆)alkyl, R¹⁵C(O)NH, R¹⁵OC(O)NH,R¹⁵NHC(O)NH, (C₁-C₆)alkyl-S(O)_(m), (C₁-C₆)alkyl-S(O)_(m)-(C₁-C₆)alkyl,R¹⁵R¹⁶NS(O)_(m), R¹⁵R¹⁶NS(O)_(m) (C₁-C₆)alkyl, R¹⁵S(O)_(m) R¹⁶N,R¹⁵S(O)_(m)R¹⁶N(C₁-C₆)alkyl wherein m is 0, 1 or 2 and R¹⁵ and R¹⁶ areeach independently selected from hydrogen or (C₁-C₆)alkyl; R² and R³ areeach independently selected from the group consisting of hydrogen,deuterium, amino, halo, hydoxy, nitro, carboxy, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, trifluoromethyl, trifluoromethoxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₃-C₁₀)cycloalkyl wherein the alkyl, alkoxy orcycloalkyl groups are optionally substittued by one to three groupsselected from halo, hydroxy, carboxy, amino (C₁-C₆)alkylthio,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₅-C₉)heteroaryl,(C₂-C₉)heterocycloalkyl, (C₃-C₉)cycloalkyl or (C₆-C₁₀)aryl; or R² and R³are each independently (C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkoxy,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₆-C₁₀)arylamino,(C₁-C₆)alkylthio, (C₆-C₁₀)arylthio, (C₁-C₆)alkylsulfinyl,(C₆-C₁₀)arylsulfinyl, (C₁-C₆)alkylsulfonyl, (C₆-C₁₀)arylsulfonyl,(C₁-C₆)acyl, (C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyamino-CO—,(C₅-C₉)heteroaryl, (C₂-C₉)heterocycloalkyl or (C₆-C₁₀)aryl wherein theheteroaryl, heterocycloalkyl and aryl groups are optionally substitutedby one to three halo, (C₁-C₆)alkyl, (C₁-C₆)alkyl-CO—NH—,(C₁-C₆)alkoxy-CO—NH—, (C₁-C₆)alkyl-CO—NH—(C₁-C₆)alkyl,(C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—(C₁-C₆)alkoxy,carboxy, carboxy(C₁-C₆)alkyl, carboxy(C₁-C₆)alkoxy,benzyloxycarbonyl(C₁-C₆)alkoxy, (C₁-C₆)alkoxycarbonyl(C₁-C₆)alkoxy,(C₆-C₁₀)aryl, amino, amino(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonylamino,(C₆-C₁₀)aryl(C₁-C₆)alkoxycarbonylamino, (C₁-C₆)alkylamino,((C₁-C₆)alkyl)₂amino, (C₁-C₆)alkylamino(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino(C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, carboxy,carboxy(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkoxycarbonyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy-CO—NH—,(C₁-C₆)alkyl-CO—NH—, cyano, (C₅-C₉)heterocycloalkyl, amino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—, ((C₁-C₆)alkyl)₂amino-CO—NH—,(C₆-C₁₀)arylamino-CO—NH—, (C₅-C₉)heteroarylamino-CO—NH—,(C₁-C₆)alkylamino-CO—NH—(C₁-C₆)alkyl,((C₁-C₆)alkyl)₂amino-CO—NH—(C₁-C₆)alkyl,(C₆-C₁₀)arylamino-CO—NH—(C₁-C₆)alkyl,(C₅-C₉)heteroarylamino-CO—NH—(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonyl,(C₁-C₆)alkylsulfonylamino, (C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl,(C₆-C₁₀)arylsulfonyl, (C₆-C₁₀)arylsulfonylamino,(C₆-C₁₀)arylsulfonylamino(C₁-C₆)alkyl, (C₁-C₆)alkylsulfonylamino,(C₁-C₆)alkylsulfonylamino(C₁-C₆)alkyl, (C₅-C₉)heteroaryl or(C₂-C₉)heterocycloalkyl.
 2. A compound according to claim 1, wherein ais 0; b is 1; X is carbonyl; c is 0; d is 0; e is 0; f is 0; and g is 0.3. A compound according to claim 1, wherein a is 0; b is 1; X iscarbonyl; c is 0; d is 1; e is 0; f is 0, and g is
 0. 4. A compoundaccording to claim 1, wherein a is 0; b is 1; X is carbonyl; c is 1; dis 0; e is 0; f is 0; and g is
 0. 5. A compound according to claim 1,wherein a is 0; b is 1; X is —C(═N=cyano)-; c is 1; d is 0; e is 0; f is0; and g is
 0. 6. A compound according to claim 1, wherein a is 0; b is0; c is 0; d is 0; e is 0; f is 0; g is 1; and Z is —C(O)—O—.
 7. Acompound according to claim 1, wherein a is 0; b is 1; X is S(O)_(n); nis 2; c is 0; d is 0; e is 0; f is 0; and g is
 0. 8. A compoundaccording to claim 1, wherein a is 0; b is 1; X is S(O)_(n); n is 2; cis 0; d is 2; e is 0; f is 1; g is 1; and Z is carbonyl.
 9. A compoundaccording to claim 1, wherein a is 0; b is 1; X is S(O)_(n); n is 2; cis 0; d is 2; e is 0; f is 1; and g is
 0. 10. A compound according toclaim 1, wherein a is 0; b is 1; X is carbonyl; c is 1; d is 0; e is 1;Y is S(O)_(n); n is 2; f is 0; and g is
 0. 11. A compound according toclaim 1, wherein a is 0; b is 1; X is S(O)_(n); n is 2; c is 1; d is 0;e is 0; f is 0; and g is
 0. 12. A compound according to claim 1, whereina is 1; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is0.
 13. A compound according to claim 1, wherein a is 0; b is 1; X isS(O)_(n); c is 0; d is 1; e is 1; Y is S(O)_(n); n is 2; f is 0; and gis
 0. 14. A compound according to claim 1, wherein a is 0; b is 1; X isS(O)_(n); c is 0; d is 2,3or 4; e is 1; Y is S(O)_(n); n is 2; f is 1;and g is
 0. 15. A compound according to claim 1, wherein a is 0; b is 1;X is oxygen; c is 0; d is 2, 3 or 4; e is 1; Y is S(O)_(n); n is 2; f is1; and g is
 0. 16. A compound according to claim 1, wherein a is 0; b is1; X is oxygen; c is 0; d is 2,3 or 4; e is 1; Y is S(O)_(n); n is 2; fis 0; and g is
 0. 17. A compound according to claim 1, wherein a is 0; bis 1; X is carbonyl; c is 1; d is 2, 3 or 4; e is 1; Y is S(O)_(n);f is0; and g is
 0. 18. A compound according to claim 1, wherein a is 0; b is1; X is carbonyl; c is 1; d is 2,3 or 4; e is 1; Y is S(O)_(n); n is 2;f is 1; and g is
 0. 19. A compound according to claim 1, wherein R¹² iscyano, trifluoromethyl, (C₁-C₆)alkyl, trifluoromethyl(C₁-C₆)alkyl,(C₁-C₆)alkylamino, ((C₁-C₆)alkyl)₂amino, (C₂-C₆)alkynyl,cyano(C₁-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(m) wherein m is 0, 1 or
 2. 20. Acompound according to claim 1, wherein said compound is selected fromthe group consisting of:Methyl-[4-methyl-1-(propane-1-sulfonyl)-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid methyl ester;3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxylicacid dimethylamide;({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carbonyl}-aminoacid ethyl ester;3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile;3,3,3-Trifluoro-1-{4-methyl-3-[methyl-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-propan-1-one;1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-but-3-yn-1-one;1-{3-[(5-Chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-piperidin-1-yl}-propan-1-one;1-{3-[(5-Fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-methyl-amino]-4-methyl-piperidin-1-yl}-propan-1-one;N-cyano-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-N′-propyl-piperidine-1-carboxamidine;andN-cyano-4,N′,N′-Trimethyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidine-1-carboxamidine.21. A pharmaceutical composition for (a) treating or preventing adisorder or condition selected from organ transplant rejection, xenotransplation, lupus, multiple sclerosis, rheumatoid arthritis,psoriasis, Type I diabetes and complications from diabetes, cancer,asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerativecolitis, Crohn's disease, Alzheimer's disease, leukemia and otherautoimmune diseases or (b) the inhibition of protein kinases or JanusKinase 3 (JAK3) in a mammal, including a human, comprising an amount ofa compound of claim 1 or a pharmaceutically acceptable salt thereof,effective in such disorders or conditions and a pharmaceuticallyacceptable carrier.
 22. A pharmaceutical composition for (a) treating orpreventing a disorder or condition selected from organ transplantrejection, xeno transplation, lupus, multiple sclerosis, rheumatoidarthritis, psoriasis, Type I diabetes and complications from diabetes,cancer, asthma, atopic dermatitis, autoimmune thyroid disorders,ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia andother autoimmune diseases or (b) the inhibition of protein kinases orJanus Kinase 3 (JAK3) in a mammal, including a human, comprising anamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof, alone or in combination with one or more additional agentswhich modulate a mammalian immune system or with antiinflammatoryagents, effective in such disorders or conditions and a pharmaceuticallyacceptable carrier.
 23. A method for the inhibition of protein kinasesor Janus Kinase 3 (JAK3) in a mammal, including a human, comprisingadministering to said mammal an effective amount of a compound of claim1 or a pharmaceutically acceptable salt thereof.
 24. A method fortreating or preventing a disorder or condition selected from organtransplant rejection, xeno transplation, lupus, multiple sclerosis,rheumatoid arthritis, psoriasis, Type I diabetes and complications fromdiabetes, cancer, asthma, atopic dermatitis, autoimmune thyroiddisorders, ulcerative colitis, Crohn's disease, Alzheimer's disease,leukemia and other autoimmune diseases in a mammal, including a human,comprising administering to said mammal an amount of a compound of claim1 or a pharmaceutically acceptable salt thereof, effective in treatingsuch a condition.
 25. A method for the inhibition of protein kinases orJanus Kinase 3 (JAK3) in a mammal, including a human, comprisingadministering to said mammal an effective amount of a compound of claim1 or a pharmaceutically acceptable salt thereof alone or in combinationwith one or more additional agents which modulate a mammalian immunesystem or with antiinflammatory agents.
 26. A method for treating orpreventing a disorder or condition selected from organ transplantrejection, xeno transplation, lupus, multiple sclerosis, rheumatoidarthritis, psoriasis, Type I diabetes and complications from diabetes,cancer, asthma, atopic dermatitis, autoimmune thyroid disorders,ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia andother autoimmune diseases in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of claim 1 or apharmaceutically acceptable salt thereof, alone or in combination withone or more additional agents which modulate a mammalian immune systemor with antiinflammatory agents, effective in treating such a condition.